Medications designed to diminish the psychologically rewarding effects of methamphetamine (METH) use could offer substantial protective effects for patients trying to cease METH use, especially if these medications could reduce the medical setbacks caused by recidivism. Anti-METH monoclonal antibody medicines that tightly bind METH in the bloodstream and sequester METH away from its site(s) of action in the brain are showing promise as a viable medical therapy. Importantly anti-METH antibodies are non-addicting, long acting and suitable for use in combination with existing behavioral therapies for METH addiction. The aims of this project are to integrate innovative medical breakthroughs in antibody engineering and gene therapy technology, to generate a long-acting antibody-based medicine that will both protect patients from relapse to METH use and minimize treatment failures associated with long-term patient compliance. We will achieve these goals by utilizing adeno-associated virus (AAV) particles to deliver genes encoding high-affinity anti- METH antibody fragments discovered by our research team. We envision that AAV-mediated gene transfer could be used to deliver these purposely designed single chain variable fragment (scFv) antibodies, which have precise specificity and high affinity for METH. The specific aims include 1) use of molecular engineering techniques to strategically design therapeutic anti-METH scFv medications suitable for packaging the encoding DNA into AAV particles for gene therapy, 2) conduct pharmacokinetic studies of these AAV-scFvs and METH to objectively determine the ability of these AAV-delivered anti-METH antibody fragments to safely and favorably alter METH disposition in rodent models, 3) examine the ability of gene therapy to safely mitigate METH-induced locomotor and cardiovascular effects in rats, 4) determine the efficacy of METH abuse gene therapy in preventing relapse to METH abuse in rat behavioral models. By the end of these studies, we will know if gene therapy can safely deliver sustained doses of antibody medications sufficient to significantly reduce METH pharmacological effects. If successful, these well-integrated approaches could provide a significant medical breakthrough in the treatment options for METH addicted patients.